A number of .alpha.-L-aspartyl, dipeptide esters are known to be intensely sweet and useful as sweeteners. R. Mazur et al., J. Am. Chem. Soc. 91, 2684-2691 (1969); U.S. Pat. Nos. 3,920,626; 3,492,131 and 3,475,403. Among these, aspartame (.alpha.-L-aspartyl-L-phenylalanine methyl ester) is now being used extensively in the food and beverage industries.
.alpha.-L-glutamyl-L-asparagine, and pharmaceutically acceptable salts thereof, are known to be therapeutically useful as immunopotentiating agents in humans and other mammals. U.S. Pat. No. 4,426,324.
A number of methods of making aspartame and the other .alpha.-L-aspartyl, dipeptide ester sweeteners are also known. See, for example, the references cited above in connection with dipeptide ester sweeteners, as well as Vinick and Jung, Tetrahedron Lett. 23, 1315-1318 (1982), and U.S. Pat. Nos. 3,962,207; 3,833,553; 3,798,206 and 3,786,039.
Several methods for making aspartame and other lower alkyl esters of .alpha.-L-aspartyl phenylalanine have been disclosed wherein a strong acid salt of L-aspartic anhydride is reacted with the methyl, or other lower alkyl, ester of L-phenylalanine or an acid solution thereof, see U.S. Pat. Nos. 3,962,207; 3,833,553; 3,798,206 and 3,786,039. A problem encountered in such syntheses is that the reactivity of the .beta.-carboxyl of the aspartic anhydride with the amino group of the phenylalanine ester is approximately one quarter to the same as that of the .alpha.-carboxyl, unless the reaction is run under conditions which enhance the reactivity of the .alpha.-carboxyl relative to that of the .beta.-carboxyl. The product resulting from condensation of the .beta.-carboxyl, .beta.-L-aspartyl phenylalanine methyl ester, is bitter and, therefore, an undesirable contaminant in aspartame preparations. It has been found that reacting strong acid salts of L-aspartic anhydride with L-phenylalanine lower alkyl esters in the presence of weak acids reduces the reactivity of the .beta.-carboxyl of the aspartic anhydride, relative to that of the .alpha.-carboxyl, by as much as 50% and, further, increases the total yield of both of the dipeptide esters, see U.S. Pat. No. 3,833,553.
The use of oxime and ketoxime esters of covalently protected amino acids in peptide synthesis is known. See, e.g., Hayashi and Shimizu, Bull. Chem. Soc. Japan 56, 3197-3198 (1983); Fujino and Nishimura, Chem. Pharm. Bull. 17, 1937 (1969). Aminolysis of oxime and ketoxime esters of covalently protected amino acids with amino acid esters, and catalysis of such aminolysis with weak acids, such as acetic acid or formic acid, are known. See, e.g., Hayashi and Shimizu, supra.
The use in solid-phase peptide synthesis of amino acid ketoxime ester-derivatized polystyrene resins has been reported, wherein the polymer-supported amino acid residues have protecting groups covalently bound to their amino groups and the corresponding ketoxime is formed with a phenyl group of the polystyrene support and a phenyl group, or substituted phenyl group selected from p-nitro, p-chloro and p-methoxy phenyl, provided by acylation of the polystyrene phenyl group with a benzoyl, or p-substituted benzoyl, halide. DeGrado and Kaiser, J. Org. Chem. 45, 1295-1300 (1980); DeGrado and Kaiser, J. Org. Chem. 47, 3258-3261 (1982); Nakagawa and Kaiser, J. Org. Chem. 48, 678-685 (1983). Aminolysis with amino acid esters of the polymer-supported, p-nitrobenzophenone ketoxime esters of covalently protected amino acids and peptides, and catalysis of such aminolysis with acetic acid, have also been reported. DeGrado and Kaiser, 1980 and 1982, supra; Nakagawa and Kaiser, 1983, supra.
Ketoxime esters of aspartic acid and glutamic acid, without protecting groups covalently bound to the amino group or unesterified carboxyl group, have not been known heretofore.